A first glimpse at the structure of an important drug target is reported online this week in Nature Chemical Biology. The enzyme ― PI(3)K ― has been implicated in a wide range of diseases including cancer and immunological diseases and a number of inhibitors have entered clinical trials. It’s hoped the research will provide important insights for designing better drug candidates.

There are a number of closely related variants, or ‘isoforms’, of PI(3)K and it is becoming clear that the specificity of inhibitors for these isoforms will affect the therapeutic potential of drug candidates. Roger Williams and colleagues now report the first crystal structure of a specific isoform of a PI(3)K ― the delta isoform ― both by itself and in complex with a wide range of isoform-selective and non-selective drugs that inhibit its function. Together, these structures reveal clues as to how these inhibitors achieve both potency and selectivity.

The PI(3)K delta isoform has been particularly implicated in immune inflammation, leukemias and some additional cancers and these structural insights are expected to open up better drug leads for these diseases.